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Qinyue Chen,1Huihui Liang,1Yali Sun,1Yiting Chen,1Wenxiu He,1Xiaoling Fang,1Xianyi Sha,1Jinming Li2 1Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, People’s Republic of China; 2Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, People’s Republic of ChinaCorrespondence: Xianyi ShaKey Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, People’s Republic of ChinaTel +86 215 198 0072Fax +86 215 198 0072Email shaxy@fudan.edu.cnJinming LiDepartment of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, People’s Republic of ChinaTel +86 212 507 7855Email lijinming@xinhuamed.com.cnPurpose: To deliver the chemotherapeutics through the nanoparticles, the delivery system should accumulate at the tumor site first and then penetrate through the interstitium into the interior. The specific tumor-targeting pathway mediated via the receptor-ligand binding could achieve the desirable accumulation of nanoparticles, and the nanoparticles with smaller sizes were required for penetration.Methods and materials: We constructed a size-shrinkable nanocluster modified with a tumor-targeting motif IF-7 (IF-7-MNC) based on a pH-sensitive framework which could be disintegrated in an acid environment to release the micelles aggregated inside. The micelles were constructed by amphiphilic block copolymers PEG−PLA to encapsulate paclitaxel (PTX), while the cross-linked framework consisting of TPGS-PEI was used as a net to gather and release micelles. This nanoplatform could specifically bind with the tumor receptor Annexin A1 through the ligand IF-7 and then shrunk into small micelles with a desirable size for penetration.Conclusion: IF-7-MNC of 112.27±6.81 nm could shrink into micelles in PBS (0.01 M, pH 5.0) with sizes of 14.89±0.32 nm. The cellular-uptake results showed that IF-7-MNC could be significantly internalized by A549 cells and HUVEC cells, while the penetration of IF-7-MNC could be more prominent into the 3D-tumor spheroids compared with that of MNC. The biodistribution results displayed that the fluorescence of IF-7-MNC in the tumor site at 24 hrs was 4.5-fold stronger than that of MNC. The results of anti-tumor growth demonstrated that IF-7-MNC was more favorable for the tumor therapy than MNC, where the inhibitory rate of tumor growth was 88.29% in the PTX-loaded IF-7-MNC (IF-7-PMNC) treated group, significantly greater than PMNC treatment group (p